1. Field of the Disclosure
This disclosure is in the fields of medicine and immunology. The disclosure provides methods of treating, ameliorating, or preventing diseases or disorders responsive to the number of T-lymphocytes in a subject, and methods of providing hepatoprotection in a subject, comprising administering a therapeutically effective amount of a β-hydroxy-γ-aminophosphonate or β-amino-γ-aminophosphonate to the subject. Diseases and disorders responsive to the number of T-lymphocytes in a subject include immune disorders, allergic disorders, and inflammatory disorders, or combinations thereof.
2. Related Art
Autoimmune and inflammatory diseases affect more than fifty million Americans. The immune system functions as the body's major defense against diseases caused by invading organisms. This complex system fights disease by killing invaders such as bacteria, viruses, parasites or cancerous cells while leaving the body's normal tissues unharmed. The immune system's ability to distinguish the body's normal tissues, or self, from foreign or cancerous tissue, or non-self, is an essential feature of normal immune system function. A second essential feature is memory, the ability to remember a particular foreign invader and to mount an enhanced defensive response when the previously encountered invader returns. The loss of recognition of a particular tissue as self and the subsequent immune response directed against that tissue produce serious illness.
Inflammation is involved in a large number of physiological and pathological conditions affecting animals and humans. Inflammatory responses can usually be traced to an immune response to an antigen, allergen, irritant, endotoxin, or to tissue damage. The process is complex, involving a large number of components, many of which display pleiotropic effects, many of which are amplifiers or inhibitors of other components. While many instances of an inflammatory response are well-controlled and self-limited, many pathologic conditions arise from uncontrolled or inappropriate responses, resulting in both acute and chronic conditions.
The immune system when operating normally is involved in precise functions such as recognition and memory of, specific response to, and clearance of, foreign substances (chemical and cellular antigens) that either penetrate the protective body barriers of skin and mucosal surfaces (transplanted tissue and microorganisms such as bacteria, viruses, parasites) or arise de novo (malignant transformation). The arsenal of the immune response is composed of two major types of lymphocytes that are either B-lymphocytes (B cells, responsible for producing antibodies which attack the invading microorganisms) or the T-lymphocytes (T cells, responsible for eliminating the infected or abnormal target cells) in cooperation with macrophages.
An autoimmune disease results from an inappropriate immune response directed against a self antigen (an autoantigen), which is a deviation from the normal state of self-tolerance. Self-tolerance arises when the production of T cells and B cells capable of reacting against autoantigens has been prevented by events that occur in the development of the immune system during early life. Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation
There is at present no cure for autoimmune diseases. However, there are a number of traditional approaches to treating autoimmune-related disorders and cancers that are known in the art. Immune responses to therapeutic agents are wide ranging, and can be directed against agents that are both non-human and human in origin. These responses include those that elicit a weak clinical effect and those that limit efficacy which can occasionally result in morbidity or even mortality in subjects. In particular, serious complications can arise with the production of neutralizing antibodies, especially when they target recombinant self proteins and therefore have the potential to cross react with the subject's own endogenous protein (Lim, Hematology 10:255-259 (2005)). Problems associated with immunogenicity to biologics, especially monoclonal antibodies, have been reduced largely due to advances in molecular biology. There are, however, many recombinant protein biologics that are identical to endogenously expressed human sequences that still elicit potent neutralizing immune responses in subjects (Hochuli, J. Interferon Cytokine Res. 17 Suppl. 1:S15-21 (1997); Schellekens et al., J. Interferon Cytokine Res. 17 Suppl. 1:S5-S8 (1997); Namaka et al., Curr. Med. Res. Opin. 22:223-239 (2006)). The mechanism by which immunogenicity is triggered remains unclear although the tolerance to self proteins may be broken by a number of factors linked to both the product and the subject (Chester et al., Expert Rev. Clin. Immunol. 1:549-559 (2006); Baker and Jones, Curr. Opin. Drug Disc. Dev. 10:219-227 (2007)). For the product, these include dose, frequency of administration, route, immunomodulatory capacity of the protein therapeutic, and the formulation (Jaber and Baker, J. Pharm. Biomed. Anal. 43:1256-1261 (2007)). For the subject, factors such as immune competence (i.e., whether the subject is receiving immunosuppressive treatment), subject's MHC haplotype and intrinsic tolerance to the protein therapeutic will influence immunogenicity. Regardless of how immunogenicity is triggered, one of the single most important factors in the development of an ensuing immune response is the presence of epitopes that are able to effectively stimulate a potent CD4+ T cell response (Baker and Jones, Curr. Opin. Drug Disc. Dev. 10:219-227 (2007)).
T cells or T-lymphocytes are a subset of white blood cells known as lymphocytes. (The abbreviation “T” in T cell is for “thymus” since this is the primary organ responsible for T cell maturation.) T cells play a central role in cell-mediated immunity. They can be distinguished from other types of lymphocytes (such as B cells and natural killer cells (NK cells)), by the presence of cell-surface proteins called T cell receptors (TCRs). Different types of T cells have also been identified; these can be distinguished based on the differing functions they serve (e.g., CD4+ T cells (a.k.a., TH or T helper cells), CD8+ cytotoxic T cells (CTLs), memory T cells, regulatory T cells (Treg cells), natural killer cells (NK cells), and gamma delta T cells (γδ T cells)).
TH cells are so named because they aid other white blood cells in immunologic processes including, inter alia, assisting the maturation of B cells into plasma and B memory cells, and activation of cytotoxic T cells and macrophages. TH cells are also known as CD4+ T cells because they express CD4 protein on the cell-surface. Once activated, CD4+ T cells divide rapidly and secrete chemokines that further assist in activating or regulating immune responses.
Experimental evidence suggests that HIV-infected patients given L-carnitine in combination with standard antiretroviral treatment have greater improvement in CD4+ counts when compared to control patients given antiretroviral agents with no supplementation (Gomez-Solis et al., Pharmacology 88:10-17 (2011)). Acetylcarnitine has also been reported to have immunomodulating activity (U.S. Pat. No. 4,415,588).